ORIGINAL ARTICLE
Conversion From Twice-Daily to Once-Daily Tacrolimus Does Not Reduce Intrapatient Variability in Tacrolimus Exposure Nauras Shuker, PharmD,* Monique Cadogan,† Teun van Gelder, MD, PhD,*† Joke I. Roodnat, MD, PhD,† Marcia M. L. Kho, MD,† Willem Weimar, MD, PhD,† and Dennis A. Hesselink, MD, PhD†
Background: Intrapatient variability (IPV) in tacrolimus exposure
Both drugs had similar IPVs (Tac-TD: 17.3% 6 1.6% versus TacOD: 16.4% 6 1.6%, P = 0.31).
is associated with renal allograft failure. The aim of this study was to investigate whether conversion from the twice-daily tacrolimus formulation (Tac-TD) to a once-daily formulation (Tac-OD) leads to a lower IPV in tacrolimus exposure.
Conclusions: Although conversion from Tac-TD to Tac-OD significantly reduces tacrolimus exposure as measured by C0 and seems safe, it does not reduce IPV in tacrolimus exposure.
Methods: Two hundred forty-seven stable renal transplant
Key Words: intrapatient variability, modified release, pharmacokinetics, tacrolimus
recipients were converted from Tac-TD to Tac-OD (Advagraf) on a 1:1-mg total daily dose basis. After conversion, patients were followed for 12 months and tacrolimus predose whole-blood concentrations (C0), serum creatinine, estimated glomerular filtration rate, and proteinuria were measured. These parameters were compared with those collected at all outpatient visits in the 12-month period (63 months) before conversion (Tac-TD period). The IPV was calculated based on the dose-adjusted tacrolimus C0.
Results: The Tac-OD formulation provided an excellent graft survival (100%), a low acute rejection rate (0.8%), and good tolerability. Renal function remained stable: estimated glomerular filtration rate 48 (16–90) versus 46 (12–90) mL/min (P = 0.15) before and after conversion, respectively. After conversion to TacOD, mean C0 was significantly lower, decreasing from 5.7 6 1.5 to 5.0 6 1.5 ng/mL, corresponding to a 12% reduction (P , 0.01). Received for publication May 1, 2014; accepted August 19, 2014. From the *Department of Hospital Pharmacy, Clinical Pharmacology Unit; and †Department of Internal Medicine, Division of Nephrology and Renal Transplantation, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Supported by Astellas Pharma Inc. N. Shuker participated in performing the research, analyzing data, and writing the article. M. Cadogan participated in performing the research and writing the article. T. V. Gelder contributed to the research design and participated in performing the research and revision of the article. J. I. Roodnat participated in performing the research and revision of the article. M. M. L. Kho participated in performing the research and revision of the article. W. Weimar contributed to the research design and participated in performing the research and revision of the article. D. A. Hesselink contributed to the research design and participated in performing the research and writing the article. T. V. Gelder has received lecture fees from Astellas Pharma. D. A. Hesselink has received lecture fees from Astellas Pharma. The other authors declare no conflict of interest. Correspondence: Nauras Shuker, PharmD, Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus MC, University Medical Center, Room Na-206, PO Box 2040, 3000 CA Rotterdam, The Netherlands (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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(Ther Drug Monit 2015;37:262–269)
INTRODUCTION Nonadherence to immunosuppressive drug treatment is associated with poor long-term transplantation outcome.1,2 Modified-release oral dosage form of tacrolimus [once-daily Tac formulation (Tac-OD), Advagraf] provides a once-daily dosing alternative for the immediate-release (twice-daily) Tac formulation (Tac-TD) and significantly improves adherence.3 The intrapatient variability (IPV) in a drug’s pharmacokinetics is the amount of fluctuation in drug concentrations within an individual over a certain period of time during which the dose is unchanged. A high IPV in the exposure to tacrolimus may put the patient at risk for toxicity (in case of overexposure) or for rejection if concentrations fall below the lower threshold of its narrow therapeutic window.4 In renal transplant recipients (RTRs), a high IPV in tacrolimus exposure is a risk factor for rejection and long-term treatment failure.5,6 Medication adherence may be an important determinant of IPV in drug exposure. Theoretically, the higher adherence to Tac-OD could lower IPV in tacrolimus exposure and improve transplantation outcomes. Only a few studies, including limited patient numbers, have compared the IPV between Tac-TD and Tac-OD.7–11 This prompted us to investigate whether conversion from Tac-TD to Tac-OD results in a lower tacrolimus IPV in a larger cohort of stable RTRs.
PATIENTS AND METHODS Study Design This was a single-center nonrandomized study to assess the safety of conversion from Tac-TD to Tac-OD after kidney transplantation. Patients were eligible for enrollment if they met the following inclusion criteria: (1) treatment with Ther Drug Monit Volume 37, Number 2, April 2015
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Intrapatient Variability in Tacrolimus Exposure
a Tac-TD–based immunosuppressive regimen, (2) a need for continued therapy with tacrolimus, (3) age $18 years, and (4) a follow-up of $5 months after transplantation. After inclusion, Tac-TD (Prograf; Astellas Pharma, Leiden, The Netherlands) was converted (t = 0) to Tac-OD (Advagraf; Astellas Pharma; only morning dosing) on a 1:1 (milligram:milligram) basis. During both study periods (preconversion and postconversion), tacrolimus doses were adjusted to achieve a predose whole-blood concentrations (C0) of 4–10 ng/mL. After conversion, patients were followed for 12 months with study assessments and laboratory sampling (tacrolimus C0 and renal function) at 3 monthly intervals or whenever deemed necessary by the attending physician. Variables of interest were tolerability of Tac-OD, renal function, and serious adverse events (SAEs). Clinicians were allowed to monitor tacrolimus exposure and adjust the Tac-OD dose before the first scheduled study visit at month 3. Within the framework of this study, we studied whether conversion from Tac-TD to Tac-OD influenced Tac IPV. We therefore collected all Tac C0 measured during visits to the outpatient clinic from the time of conversion up until month 12 (61 month) after conversion (t = 12). To calculate Tac IPV during the use of Tac-TD, we collected the Tac C0 retrospectively from the year before conversion (t = 212 6 3 months). As transplant recipients are not on a stable Tac dose in the first phase after transplantation and because they often underwent interventions that may influence Tac exposure in this period (eg, the use of interacting antibiotics or pulse corticosteroid therapy), only data on Tac exposure from month 5 (and onward) posttransplantation were considered. Therefore, data on the Tac IPV were derived from patients at least 14 months after transplantation. For the same reason, Tac C0 that were collected during hospital admission(s) were not included.
integer (absolute value). Because not all patients received a constant Tac dose throughout the study period, the obtained Tac C0 were corrected for the corresponding daily Tac dose (C0/D). The reciprocal of this ratio gives an apparent oral clearance. Patients were characterized as having a high or low IPV using the median variability of the IPV as the cutoff value. Tacrolimus C0 were determined in whole blood using the ACMIA-Flex immunoassay on a Dimension XPand (both Siemens HealthCare Diagnostics Inc, Newark, NJ).
Ethics
where st is the SD, ƿ the correlation between 2 measures, and
The study was approved by the institutional review board. The conversion from Tac-TD to Tac-OD was considered to be in the realm of routine clinical care, and therefore, no formal medical ethical approval of this study was required. Nonetheless, all patients were asked if they objected to being switched to Tac-OD, and all gave written consent before conversion. For the study of the change in Tac IPV, data were used that were only obtained as part of the routine patient care.
Intrapatient Variability The variable of interest was the Tac IPV. For its calculation, at least 3 Tac C0 measurements had to be available for both the Tac-TD and the Tac-OD phases. IPV was calculated as follows:5
Statistical Analyses The IPV was calculated using Microsoft Excel 2010. Statistical analyses were performed using Statistical Program of Social Sciences version 20 (SPSS Inc, Chicago, IL). Data distribution was assessed by visual inspection and the Kolmogorov–Smirnov test. As the distribution was mostly skewed, the log-transformed data were analyzed. Categorical variables are reported using frequency tables and percentages, and continuous variables are expressed as geometric means, unless stated otherwise. Differences in IPV between the treatment periods were assessed using the paired t test. Differences in median values were tested by the Wilcoxon signed-rank test, and distributions were tested by the Mann–Whitney U test. The relationship between various demographic, clinical, and laboratory variables with Tac IPV was assessed using univariate analyses. Variables that showed a statistically significant relation were then included in a multivariate regression analysis to investigate if they affected the relation between the formulation and IPV. To quantify the effect of regression to the mean (RTM), the following formula was used:12,13 RTM effect ¼ st ð1 2 rÞCðzÞ; 2 1#r#1;
(2)
CðzÞ ¼ fðzÞ=ð1 2 FðzÞÞ; where z = (c 2 population mean)/st if the subjects are selected using a baseline measurement greater than c and z = (population mean 2 c)/st if the subjects are selected using a baseline measurement less than c. The terms f(z) and 1 2 F(z) are, respectively, the probability density and the cumulative distribution functions of the standard normal distribution. The calculations were undertaken using the log-transformed data. Statistical significance was defined as a 2-tailed P ,0.05. The post hoc power calculation was performed using the program “G*power 3.1.9.2” (Heinrich-Hein-University, Düsseldorf, Germany).
IPV% ¼ f½jðXmean 2 X1 Þj þ jðXmean 2 X2 Þj. þ jðXmean 2 Xn Þj=ng=Xmean · 100;
(1)
RESULTS
where Xmean is the mean Tac C0 of all available samples, X1 is the first available Tac concentration measurement, X2 is the second, and Xn is the nth available Tac C0. Using this formula, the quantity (Xmean 2 Xn) is always expressed as a positive
Baseline Characteristics and Pharmacokinetic Outcomes
Two hundred fifty-one stable RTRs were enrolled between December 2009 and October 2011 (Table 1 for
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TABLE 1. Patient Demographics and Baseline Characteristics Number of Subjects (%) Sex Male/female Age (yrs) Ethnicity White Black Asian Other Primary kidney disease Hypertensive nephropathy Polycystic kidney disease Diabetic nephropathy Glomerulonephritis Congenital/reflux disease Other Unknown Number of kidney transplantation First/second/third or more Donor type Living/deceased Number of HLA mismatches 0 1 2 $3 Missing Time from transplantation to conversion (mo) Immunosuppression at baseline Tac-TD (monotherapy) Tac-TD and MMF Tac-TD and prednisone Tac-TD, MMF, and prednisone Tac-TD and other immunosuppressive drugs
175 (69.7%)/76 (30.3%) 51 (18–80)* 183 28 24 16
(72.9%) (11.2%) (9.6%) (6.4%)
35 26 25 52 14 76 23
(13.9%) (10.4%) (10.0%) (20.7%) (5.6%) (30.3%) (9.2%)
207 (82.5%)/34 (13.5%)/10 (4.0%)
outside the therapeutic range (4–10 ng/mL). In the remainder (n = 23), the clinicians changed the dose because they anticipated a decrease in Tac C0 or because of Tac toxicity (side effects). Three months after conversion, 240 patients were still using Tac-OD. Their total daily Tac dose was comparable with that at the time of conversion: 4.0 6 1.8 versus 4.1 6 1.7 mg/d, P = 0.16. In the first 3 months after conversion, the daily Tac dose had been left unaltered in 149 but was increased in 51 and decreased in 40 patients based on Tac C0 measurements. Tac C0 decreased from 5.8 ng/mL at baseline to 5.1 ng/mL at month 3, corresponding to a 12% fall (P , 0.01). The doseadjusted Tac C0 (C0/D) also decreased by 14% (P , 0.01, Table 2). The analysis was repeated after exclusion of the 36 patients who were not converted on a 1:1 basis. Again, Tac C0 decreased significantly, decreasing from 5.7 to 5.0 ng/mL or by 12% (P , 0.01). Tac C0/D decreased from 1.43 to 1.25 ng/mL per mg/d (P , 0.01).
Clinical Outcomes
characteristics). Of these, 247 were converted to Tac-OD. Three patients never took Tac-OD for unknown reasons, and 1 patient declined conversion after signing informed consent. Of these 247 patients, 227 completed the 12-month follow-up (Fig. 1). During follow-up, 2 patients died, 5 were lost to follow-up, and in 13 patients treatment with Tac-OD was interrupted (in 8 cases because of side effects, in 4 for unknown reasons). These 12 patients were reconverted to Tac-TD. In 1 patient, treatment with Tac-OD was interrupted because of recurrent glomerulonephritis requiring cyclophosphamide and high-dose glucocorticoid treatment. Most patients (n = 211 or 85%) were converted from Tac-TD to Tac-OD on a 1:1 (milligram:milligram) total daily dose basis. However, in 36 cases, it was decided to change the daily Tac dose at conversion and was therefore increased in 25 and decreased in 11 patients. In 13 patients, the Tac dose was changed at the time of conversion because Tac C0 was
Ninety-one SAEs occurred in 62 patients (25.1%). Patient survival was 99.2%. One patient died from liver insufficiency caused by hepatitis C virus–related cirrhosis. The second patient died of unknown cause while on holiday. Neither of these deaths was suspected to be related to the use of Tac-OD. One-year graft survival censored for death was 100%. Two patients experienced a biopsy-proven acute rejection. The first patient had a type 1 acute cellular rejection occurring some 3½ years after transplantation and 8 months after conversion to Tac-OD, which was treated with methylprednisolone. The second patient experienced a type 1 acute cellular rejection occurring 3 months after conversion. This rejection may have been triggered by the conversion to Tac-OD as Tac exposure temporarily decreased to a nadir of 3.6 ng/mL. Three patients developed nonmelanoma skin cancer. Two patients experienced recurrent primary kidney disease (1 case of IgA nephropathy and 1 of p-ANCA–associated glomerulonephritis). Twenty-six SAEs were related to hospitalization for an infection. In 56 cases, other reasons necessitated hospitalization. Fifty-seven nonsevere adverse events (AEs) occurred in 52 (21.1%) patients. The most frequently reported AEs included skin-related disorders (n = 10, 4.0%) and infections (n = 17, 6.9%), most of which were urinary tract infections (n = 10, 4.0%). Renal function and proteinuria did not change during follow-up (Table 3). Renal function of the 12 patients who discontinued Tac-OD also remained stable (data not shown). Renal function of the patients (n = 114) who had a decrease in their Tac C0 also did not change after conversion: [48 (16–90) mL/min at baseline versus 47 (15–90) mL/min at month 3 after conversion, P = 0.13, versus 47 (12–90) mL/min at month 12 after conversion, P = 0.82]. Apart from a small decrease in high-density lipoprotein cholesterol, all other clinical and laboratory parameters were unaffected (Table 3).
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175 (69.7%)/76 (30.3%) 11 23 54 157 6 37
(4.4%) (9.2%) (21.5%) (62.5%) (2.4%) (5–312)*
29 193 13 8 8
(11.6%) (76.9%) (5.2%) (3.2%) (3.2%)
*Median (range). HLA, Human leukocyte antigen; MMF, mycophenolate mofetil.
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Intrapatient Variability in Tacrolimus Exposure
FIGURE 1. Flow chart.
Tac-OD was in general tolerated well, and only 8 patients discontinued Tac-OD because of side effects. The AEs that led to the discontinuation of Tac-OD were mild and included rash (n = 2), gastrointestinal complaints (n = 2), headache (n = 1), myalgia (n = 1), insomnia (n = 1), and worsening of eczema (n = 2).
Effect of Conversion to Tac-OD on Tac IPV To analyze the influence of Tac formulation on the IPV in Tac apparent oral clearance (hereafter referred to as Tac IPV), stricter inclusion criteria were applied. Eighty patients
were excluded, leaving a total of 167 patients for the IPV analyses. In 9 cases, ,3 samples were available after conversion because these patients were reconverted to Tac-TD. Seventy-one cases were excluded because the Tac-TD treatment phase was shorter than 9 months. As observed in the whole group, a significant decrease in Tac C0 (9.5%) and in Tac C0/D (10%) occurred between conversion and month 3, despite a stable Tac daily dose (Table 2). The mean number of available samples per patient was 6.3 6 2.3 (Tac-TD period) and 5.8 6 2.5 (TacOD phase) and was slightly higher before conversion
TABLE 2. The Pharmacokinetic Parameters at Conversion (t = 0) and After Conversion to Tac-OD Whole study population (n = 247) Tac dose (mg/d) Tac C0 (ng/mL) Tac C0/dose (ng/mL per mg/d) Patients available for IPV analysis (n = 167) Tac dose (mg/d) Tac C0 (ng/mL) Tac C0/dose (ng/mL per mg/d)
t=0
Month 3
Month 6
Month 9
Month 12
n = 247 4.0 6 1.8 5.8 6 1.5 1.46 6 1.88
n = 240 4.1 6 1.7 5.1 6 1.5* 1.26 6 1.85*
n = 237 4.0 6 1.7 5.1 6 1.4* 1.27 6 1.74*
n = 234 4.0 6 1.7 5.2 6 1.4* 1.31 6 1.73*
n = 227 4.0 6 1.7 4.9 6 1.5* 1.24 6 1.81*
3.8 6 1.7 5.3 6 1.4 1.39 6 1.92
3.9 6 1.7 4.8 6 1.5* 1.25 6 1.80*
3.8 6 1.7 4.9 6 1.4* 1.27 6 1.70*
3.9 6 1.7 5.0 6 1.3 1.33 6 1.72
3.8 6 1.7 4.6 6 1.5* 1.23 6 1.84*
All values are expressed as geometric mean with SD. The apparent oral clearance is calculated by taking the reciprocal of dose-corrected Tac C0 (eg, a Tac C0/dose of 1.4 ng/mL per mg/day gives an apparent oral clearance of 0.50 L/min). *Significant change (P , 0.05) comparing with the measurements at the conversion time point (t = 0).
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TABLE 3. Evolution of Clinical and Laboratory Parameters in the 12 Months After Conversion From Tac-TD to Tac-OD Conversion Plasma creatinine (mmol/L) eGFR (mL/min) Proteinuria (g/L) Protein/creatinine (mg/mmol) Hemoglobin (mmol/L) Fasting plasma glucose (mmol/L) Triglycerides (mmol/L) Total cholesterol (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg)
132 48 0.11 14.52 8.2 5.6 1.56 4.6 1.21 2.65 135 80
(55–324) (16–90) (0.02–3.42) (4.00–551.60) (4.9–11.0) (3.9–26.7) (0.46–6.88) (1.8–7.5) (0.33–4.86) (0.34–5.44) (80–191) (50–110)
Month 12 6 1 134 46 0.10 13.51 8.3 5.6 1.57 4.5 1.20 2.70 139 80
(57–464) (12–90) (0.01–6.88) (3.97–1186.20) (5.1–11.4) (3.8–22.2) (0.45–6.76) (2.5–7.5) (0.63–3.44) (1.20–5.43) (100–200) (58–104)
P 0.38 0.26 0.80 0.57 0.35 0.98 0.45 0.41 0.04 0.59 0.65 0.91
eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; protein/creatinine, urinary protein/urinary creatinine ratio.
(P = 0.02). In both phases, interpatient variability in IPV was considerable, with some individuals having a variability of ,5% and others .50%. The median IPV for Tac-TD was 17.9% (2.9%–51.4%) and for Tac-OD 16.8% (4.2%–64.1%), P = 0.25. Conversion to Tac-OD did not result in a change in geometric mean Tac IPV: 17.3% 6 1.7% versus 16.4% 6 1.6%, for the Tac-TD and Tac-OD phases, respectively, P = 0.31. The conversion also did not alter the distribution of the IPV (P = 0.12, Fig. 2). When the 71 patients with a Tac-TD phase ,9 months were included, again Tac IPV did not change after conversion to Tac-OD: the median IPV for
Tac-TD was 16.9% (1.5%–56.1%) and for Tac-OD 16.5% (4.1%–68.5%), P = 0.71. Patients were classified using the median Tac IPV before conversion (17.9%) as the cutoff. This resulted in 83 patients being classified as having low variability (mean: 11.7% 6 1.4%) and 84 as having a high variability (mean: 25.6% 6 1.3%). Using this same cutoff, after conversion, the number of patients in the low-variability group rose from 83 to 93 (11.8% 6 1.4%), whereas 74 patients ended up in the highvariability group (24.9% 6 1.3%). Before conversion, patients with high IPV had a higher number of Tac dose changes in the
FIGURE 2. Change of distribution (by 5% intervals) of Tac IPV before and after conversion from Tac-TD to Tac-OD.
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Ther Drug Monit Volume 37, Number 2, April 2015
12 6 3-month observation period compared with patients with low IPV [median 0.5 (0–5) versus 0.0 (0–3), P = 0.02]. After conversion, there were no significant differences in the number of Tac-OD dose adjustments between the 2 groups: median 1.0 (0–4) versus 0.0 (0–3) for the low- and high-variability groups, respectively, P = 0.078. This same analysis restricted to the group of 84 patients with high variability before conversion demonstrated a significant decrease in IPV after conversion: 25.6% 6 1.3% versus 17.1% 6 1.6% (P , 0.01, Fig. 3B). This effect was even stronger when we included only those patients with an IPV in the upper quartile: IPV decreased from 31.8% 6 1.2% to 18.0% 6 1.6% in the Tac-OD phase (P , 0.01). The reverse was observed for the group of 83 patients who had a low Tac IPV before conversion: the IPV increased from 11.7% 6 1.4% (Tac-TD) to 15.8 6 1.6% (Tac-OD), P , 0.01 (Fig. 3C). Univariate analyses revealed that age, sex, time after transplantation, baseline creatinine, and hemoglobin concentration had no influence on IPV. Unfortunately, CYP3A5 genotype, which has been correlated with Tac dose requirement,14 was not available for this cohort. However, there was a direct proportional correlation between the number of samples and IPV and between the number of dose changes and IPV. In a regression analysis, the effect of switching from Tac-TD to Tac-OD on the IPV remained statistically significant at the same level after
Intrapatient Variability in Tacrolimus Exposure
adjustment for the number of dose changes and the number of samples. Subsequently, we investigated whether this observation was a treatment effect or whether it was caused by the RTM phenomenon. After conversion, patients with high variability in Tac exposure had a 0.1746 change (decrease) in IPV on the log scale, corresponding to 8.5% on normal scale. Using Equation 2 with st = 0.1263, ƿ = 0.05, population mean of 1.2386, c = 1.2538, f = 0.40, and F = 0.47, the estimated RTM effect was 0.1726 (98% of the observed decrease). Hence, it can be concluded that there was no real change in the IPV after conversion.
DISCUSSION This study demonstrates that converting stable RTRs from Tac-TD to Tac-OD is safe. Graft survival (censored for death) after conversion was 100%, and only 2 patients died from causes unrelated to the Tac formulation conversion. Renal function, proteinuria, glucose levels, and blood pressure did not change after conversion. Although a considerable number of SAEs occurred, this is not unusual for RTRs who are immunocompromised and frequently have multiple comorbidities. Tac-OD was tolerated well, treatment discontinuations because of AEs were infrequent, and drug-related side effects
FIGURE 3. The individual change of Tac IPV before and after conversion from Tac-TD to Tac-OD. A, All patients available for the IPV analysis (n = 167). B, Patients with high IPV before conversion (n = 84). C, Patients with low IPV before conversion (n = 83). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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were mild. The nonrandomized design of this study is an obvious limitation, making a formal comparison regarding the safety of both formulations impossible. However, our findings are consistent with safety data of other conversion studies9,15–17 and of the phases 2 and 3 trials.18 Industry-sponsored trials performed in both stable and de novo RTRs showed that conversion from Tac-TD to TacOD on a 1:1 (milligram:milligram) daily dose basis yields comparable drug exposure [measured as either the area under the concentration versus time curve 0–24 hours (AUC0–24) or C0].19 However, more recent reports demonstrate that conversion to Tac-OD is associated with considerably lower Tac exposure (of up to 15%), necessitating occasional dose changes.19–21 In line with the latter observations, significantly lower Tac C0 and Tac C0/D were observed after conversion in this study. These discrepancies in the changes in Tac exposure after conversion likely relate to differences in inclusion criteria of the various trials, which were stricter in the earlier trials. The present study was a “real-world” conversion study, and only a few exclusion criteria applied. Apart from 1 patient who suffered from acute rejection shortly after conversion, there were no other cases of rejection that contributed to low Tac exposure. It can be argued that the observed lowering of Tac exposure after conversion is not clinically relevant. Nevertheless, to prevent the occasional case of marked overexposure or underexposure, at our center, we routinely measure Tac C0 1–2 weeks after conversion to Tac-OD. This study shows that conversion from Tac-TD to TacOD does not result in a lower Tac IPV, confirming the findings of Wehland et al7 and van Hooff et al,11 which were conducted in smaller patient groups. Other investigators have observed a lowering of Tac IPV after conversion.8–10 An important limitation of the study of Wu et al9 is the fact that the number of samples after conversion was larger than before conversion. By mathematical principle, the estimation of IPV (or %CV) will become more precise if the number of samples increases. In the study by Stifft et al,10 Tac IPV did not change after conversion when it was calculated using C0 but decreased when it was calculated using AUC0–24. In the study by Stifft et al, the decrease in Tac IPV, calculated using AUC0–24, was 3.2%, which, although statistically significantly different, may be considered not to be clinically relevant. In the present study, we chose to evaluate Tac exposure using C0 only because of reports demonstrating a significant correlation between AUC0–24 and C0 for both Tac formulations8,10,22,23 and because Tac C0 is the therapeutic drug monitoring parameter that is used most frequently in clinical practice. A change in Tac IPV may thus have remained undetected. The present study did, however, have a power of almost 100% to detect a difference in IPV (data not shown). In patients with a high Tac variability, conversion resulted in a significantly decreased IPV. This may have been caused by improved adherence as observed by Kuypers et al.3 We did not measure patient compliance directly. However, because the observed median IPV was not very high before conversion, we feel that the rate of medication adherence in the present selected population may have been high, with
1. Dew MA, DiMartini AF, De Vito Dabbs A, et al. Rates and risk factors for nonadherence to the medical regimen after adult solid organ transplantation. Transplantation. 2007;83:858–873. 2. Butler JA, Roderick P, Mullee M, et al. Frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review. Transplantation. 2004;77:769–776. 3. Kuypers DR, Peeters PC, Sennesael JJ, et al. Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring. Transplantation. 2013;95: 333–340. 4. Kahan BD. High variability of drug exposure: a biopharmaceutic risk factor for chronic rejection. Transplant Proc. 1998;30:1639–1641. 5. Borra LC, Roodnat JI, Kal JA, et al. High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation. Nephrol Dial Transplant. 2010;25:2757–2763. 6. Ro H, Min SI, Yang J, et al. Impact of tacrolimus intraindividual variability and CYP3A5 genetic polymorphism on acute rejection in kidney transplantation. Ther Drug Monit. 2012;34:680–685. 7. Wehland M, Bauer S, Brakemeier S, et al. Differential impact of the CYP3A5*1 and CYP3A5*3 alleles on pre-dose concentrations of two tacrolimus formulations. Pharmacogenet Genomics. 2011;21:179–184. 8. Alloway R, Steinberg S, Khalil K, et al. Conversion of stable kidney transplant recipients from a twice daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen. Transplant Proc. 2005; 37:867–870. 9. Wu MJ, Cheng CY, Chen CH, et al. Lower variability of tacrolimus trough concentration after conversion from prograf to advagraf in stable kidney transplant recipients. Transplantation. 2011;92:648–652. 10. Stifft F, Stolk LM, Undre N, et al. Lower variability in 24-hour exposure during once-daily compared to twice-daily tacrolimus formulation in kidney transplantation. Transplantation. 2014;97:775–780. 11. van Hooff J, Van der Walt I, Kallmeyer J, et al. Pharmacokinetics in stable kidney transplant recipients after conversion from twice-daily to once-daily tacrolimus formulations. Ther Drug Monit. 2012;34:46–52. 12. Barnett AG, van der Pols JC, Dobson AJ. Regression to the mean: what it is and how to deal with it. Int J Epidemiol. 2005;34:215–220. 13. Davis CE. The effect of regression to the mean in epidemiologic and clinical studies. Am J Epidemiol. 1976;104:493–498.
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little potential for further improvement by conversion to Tac-OD. Alternatively, reported changes in IPV after conversion may not have been a true treatment effect but rather the result of RTM. RTM is a statistical phenomenon that can make natural variation in repeated data that seem to reflect a real change. This occurs when unusually large or small measurements tend to be followed by measurements that are closer to the mean.12,13 Indeed, about 98% of the decrease in IPV we observed was explained by RTM and therefore not the result of conversion per se. Whether the RTM phenomenon also affected the results of previous studies cannot be determined. However, the chance that this phenomenon occurs increases when a nonrandomized, controlled, or noncrossover design is followed. In conclusion, conversion from the Tac-TD to the Tac-OD formulation on the same milligram-for-milligram daily dose basis significantly reduces Tac exposure but does not lower Tac IPV. Nonetheless, conversion to Tac-OD seems to be safe.
ACKNOWLEDGMENTS The authors are grateful to Mrs. I. Buijt for her statistical advice. REFERENCES
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Intrapatient Variability in Tacrolimus Exposure
14. Hesselink DA, Bouamar R, Elens L, et al. The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2014;53:123–139. 15. Guirado L, Cantarell C, Franco A, et al. Efficacy and safety of conversion from twice-daily to once-daily tacrolimus in a large cohort of stable kidney transplant recipients. Am J Transplant. 2011;11:1965–1971. 16. Alloway R, Steinberg S, Khalil K, et al. Two years postconversion from a prograf-based regimen to a once-daily tacrolimus extended-release formulation in stable kidney transplant recipients. Transplantation. 2007; 83:1648–1651. 17. Kurnatowska I, Krawczyk J, Oleksik T, et al. Tacrolimus dose and blood concentration variability in kidney transplant recipients undergoing conversion from twice daily to once daily modified release tacrolimus. Transplant Proc. 2011;43:2954–2956. 18. Kramer BK. Tacrolimus prolonged release in kidney transplantation. Expert Rev Clin Immunol. 2009;5:127–133.
19. Barraclough KA, Isbel NM, Johnson DW, et al. Once- versus twice-daily tacrolimus: are the formulations truly equivalent? Drugs. 2011;71:1561–1577. 20. Ho ET, Wong G, Craig JC, et al. Once-daily extended-release versus twice-daily standard-release tacrolimus in kidney transplant recipients: a systematic review. Transplantation. 2013;95:1120–1128. 21. Niioka T, Satoh S, Kagaya H, et al. Comparison of pharmacokinetics and pharmacogenetics of once- and twice-daily tacrolimus in the early stage after renal transplantation. Transplantation. 2012;94:1013–1019. 22. Florman S, Alloway R, Kalayoglu M, et al. Conversion of stable liver transplant recipients from a twice-daily Prograf-based regimen to a oncedaily modified release tacrolimus-based regimen. Transplant Proc. 2005; 37:1211–1213. 23. Wlodarczyk Z, Squifflet JP, Ostrowski M, et al. Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open-label trial. Am J Transplant. 2009; 9:2505–2513.
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Conversion From Twice-Daily to Once-Daily Tacrolimus Does Not Reduce Intrapatient Variability in Tacrolimus Exposure Nauras Shuker, PharmD,* Monique Cadogan,† Teun van Gelder, MD, PhD,*† Joke I. Roodnat, MD, PhD,† Marcia M. L. Kho, MD,† Willem Weimar, MD, PhD,† and Dennis A. Hesselink, MD, PhD†
Background: Intrapatient variability (IPV) in tacrolimus exposure
Both drugs had similar IPVs (Tac-TD: 17.3% 6 1.6% versus TacOD: 16.4% 6 1.6%, P = 0.31).
is associated with renal allograft failure. The aim of this study was to investigate whether conversion from the twice-daily tacrolimus formulation (Tac-TD) to a once-daily formulation (Tac-OD) leads to a lower IPV in tacrolimus exposure.
Conclusions: Although conversion from Tac-TD to Tac-OD significantly reduces tacrolimus exposure as measured by C0 and seems safe, it does not reduce IPV in tacrolimus exposure.
Methods: Two hundred forty-seven stable renal transplant
Key Words: intrapatient variability, modified release, pharmacokinetics, tacrolimus
recipients were converted from Tac-TD to Tac-OD (Advagraf) on a 1:1-mg total daily dose basis. After conversion, patients were followed for 12 months and tacrolimus predose whole-blood concentrations (C0), serum creatinine, estimated glomerular filtration rate, and proteinuria were measured. These parameters were compared with those collected at all outpatient visits in the 12-month period (63 months) before conversion (Tac-TD period). The IPV was calculated based on the dose-adjusted tacrolimus C0.
Results: The Tac-OD formulation provided an excellent graft survival (100%), a low acute rejection rate (0.8%), and good tolerability. Renal function remained stable: estimated glomerular filtration rate 48 (16–90) versus 46 (12–90) mL/min (P = 0.15) before and after conversion, respectively. After conversion to TacOD, mean C0 was significantly lower, decreasing from 5.7 6 1.5 to 5.0 6 1.5 ng/mL, corresponding to a 12% reduction (P , 0.01). Received for publication May 1, 2014; accepted August 19, 2014. From the *Department of Hospital Pharmacy, Clinical Pharmacology Unit; and †Department of Internal Medicine, Division of Nephrology and Renal Transplantation, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Supported by Astellas Pharma Inc. N. Shuker participated in performing the research, analyzing data, and writing the article. M. Cadogan participated in performing the research and writing the article. T. V. Gelder contributed to the research design and participated in performing the research and revision of the article. J. I. Roodnat participated in performing the research and revision of the article. M. M. L. Kho participated in performing the research and revision of the article. W. Weimar contributed to the research design and participated in performing the research and revision of the article. D. A. Hesselink contributed to the research design and participated in performing the research and writing the article. T. V. Gelder has received lecture fees from Astellas Pharma. D. A. Hesselink has received lecture fees from Astellas Pharma. The other authors declare no conflict of interest. Correspondence: Nauras Shuker, PharmD, Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus MC, University Medical Center, Room Na-206, PO Box 2040, 3000 CA Rotterdam, The Netherlands (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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(Ther Drug Monit 2015;37:262–269)
INTRODUCTION Nonadherence to immunosuppressive drug treatment is associated with poor long-term transplantation outcome.1,2 Modified-release oral dosage form of tacrolimus [once-daily Tac formulation (Tac-OD), Advagraf] provides a once-daily dosing alternative for the immediate-release (twice-daily) Tac formulation (Tac-TD) and significantly improves adherence.3 The intrapatient variability (IPV) in a drug’s pharmacokinetics is the amount of fluctuation in drug concentrations within an individual over a certain period of time during which the dose is unchanged. A high IPV in the exposure to tacrolimus may put the patient at risk for toxicity (in case of overexposure) or for rejection if concentrations fall below the lower threshold of its narrow therapeutic window.4 In renal transplant recipients (RTRs), a high IPV in tacrolimus exposure is a risk factor for rejection and long-term treatment failure.5,6 Medication adherence may be an important determinant of IPV in drug exposure. Theoretically, the higher adherence to Tac-OD could lower IPV in tacrolimus exposure and improve transplantation outcomes. Only a few studies, including limited patient numbers, have compared the IPV between Tac-TD and Tac-OD.7–11 This prompted us to investigate whether conversion from Tac-TD to Tac-OD results in a lower tacrolimus IPV in a larger cohort of stable RTRs.
PATIENTS AND METHODS Study Design This was a single-center nonrandomized study to assess the safety of conversion from Tac-TD to Tac-OD after kidney transplantation. Patients were eligible for enrollment if they met the following inclusion criteria: (1) treatment with Ther Drug Monit Volume 37, Number 2, April 2015
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a Tac-TD–based immunosuppressive regimen, (2) a need for continued therapy with tacrolimus, (3) age $18 years, and (4) a follow-up of $5 months after transplantation. After inclusion, Tac-TD (Prograf; Astellas Pharma, Leiden, The Netherlands) was converted (t = 0) to Tac-OD (Advagraf; Astellas Pharma; only morning dosing) on a 1:1 (milligram:milligram) basis. During both study periods (preconversion and postconversion), tacrolimus doses were adjusted to achieve a predose whole-blood concentrations (C0) of 4–10 ng/mL. After conversion, patients were followed for 12 months with study assessments and laboratory sampling (tacrolimus C0 and renal function) at 3 monthly intervals or whenever deemed necessary by the attending physician. Variables of interest were tolerability of Tac-OD, renal function, and serious adverse events (SAEs). Clinicians were allowed to monitor tacrolimus exposure and adjust the Tac-OD dose before the first scheduled study visit at month 3. Within the framework of this study, we studied whether conversion from Tac-TD to Tac-OD influenced Tac IPV. We therefore collected all Tac C0 measured during visits to the outpatient clinic from the time of conversion up until month 12 (61 month) after conversion (t = 12). To calculate Tac IPV during the use of Tac-TD, we collected the Tac C0 retrospectively from the year before conversion (t = 212 6 3 months). As transplant recipients are not on a stable Tac dose in the first phase after transplantation and because they often underwent interventions that may influence Tac exposure in this period (eg, the use of interacting antibiotics or pulse corticosteroid therapy), only data on Tac exposure from month 5 (and onward) posttransplantation were considered. Therefore, data on the Tac IPV were derived from patients at least 14 months after transplantation. For the same reason, Tac C0 that were collected during hospital admission(s) were not included.
integer (absolute value). Because not all patients received a constant Tac dose throughout the study period, the obtained Tac C0 were corrected for the corresponding daily Tac dose (C0/D). The reciprocal of this ratio gives an apparent oral clearance. Patients were characterized as having a high or low IPV using the median variability of the IPV as the cutoff value. Tacrolimus C0 were determined in whole blood using the ACMIA-Flex immunoassay on a Dimension XPand (both Siemens HealthCare Diagnostics Inc, Newark, NJ).
Ethics
where st is the SD, ƿ the correlation between 2 measures, and
The study was approved by the institutional review board. The conversion from Tac-TD to Tac-OD was considered to be in the realm of routine clinical care, and therefore, no formal medical ethical approval of this study was required. Nonetheless, all patients were asked if they objected to being switched to Tac-OD, and all gave written consent before conversion. For the study of the change in Tac IPV, data were used that were only obtained as part of the routine patient care.
Intrapatient Variability The variable of interest was the Tac IPV. For its calculation, at least 3 Tac C0 measurements had to be available for both the Tac-TD and the Tac-OD phases. IPV was calculated as follows:5
Statistical Analyses The IPV was calculated using Microsoft Excel 2010. Statistical analyses were performed using Statistical Program of Social Sciences version 20 (SPSS Inc, Chicago, IL). Data distribution was assessed by visual inspection and the Kolmogorov–Smirnov test. As the distribution was mostly skewed, the log-transformed data were analyzed. Categorical variables are reported using frequency tables and percentages, and continuous variables are expressed as geometric means, unless stated otherwise. Differences in IPV between the treatment periods were assessed using the paired t test. Differences in median values were tested by the Wilcoxon signed-rank test, and distributions were tested by the Mann–Whitney U test. The relationship between various demographic, clinical, and laboratory variables with Tac IPV was assessed using univariate analyses. Variables that showed a statistically significant relation were then included in a multivariate regression analysis to investigate if they affected the relation between the formulation and IPV. To quantify the effect of regression to the mean (RTM), the following formula was used:12,13 RTM effect ¼ st ð1 2 rÞCðzÞ; 2 1#r#1;
(2)
CðzÞ ¼ fðzÞ=ð1 2 FðzÞÞ; where z = (c 2 population mean)/st if the subjects are selected using a baseline measurement greater than c and z = (population mean 2 c)/st if the subjects are selected using a baseline measurement less than c. The terms f(z) and 1 2 F(z) are, respectively, the probability density and the cumulative distribution functions of the standard normal distribution. The calculations were undertaken using the log-transformed data. Statistical significance was defined as a 2-tailed P ,0.05. The post hoc power calculation was performed using the program “G*power 3.1.9.2” (Heinrich-Hein-University, Düsseldorf, Germany).
IPV% ¼ f½jðXmean 2 X1 Þj þ jðXmean 2 X2 Þj. þ jðXmean 2 Xn Þj=ng=Xmean · 100;
(1)
RESULTS
where Xmean is the mean Tac C0 of all available samples, X1 is the first available Tac concentration measurement, X2 is the second, and Xn is the nth available Tac C0. Using this formula, the quantity (Xmean 2 Xn) is always expressed as a positive
Baseline Characteristics and Pharmacokinetic Outcomes
Two hundred fifty-one stable RTRs were enrolled between December 2009 and October 2011 (Table 1 for
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TABLE 1. Patient Demographics and Baseline Characteristics Number of Subjects (%) Sex Male/female Age (yrs) Ethnicity White Black Asian Other Primary kidney disease Hypertensive nephropathy Polycystic kidney disease Diabetic nephropathy Glomerulonephritis Congenital/reflux disease Other Unknown Number of kidney transplantation First/second/third or more Donor type Living/deceased Number of HLA mismatches 0 1 2 $3 Missing Time from transplantation to conversion (mo) Immunosuppression at baseline Tac-TD (monotherapy) Tac-TD and MMF Tac-TD and prednisone Tac-TD, MMF, and prednisone Tac-TD and other immunosuppressive drugs
175 (69.7%)/76 (30.3%) 51 (18–80)* 183 28 24 16
(72.9%) (11.2%) (9.6%) (6.4%)
35 26 25 52 14 76 23
(13.9%) (10.4%) (10.0%) (20.7%) (5.6%) (30.3%) (9.2%)
207 (82.5%)/34 (13.5%)/10 (4.0%)
outside the therapeutic range (4–10 ng/mL). In the remainder (n = 23), the clinicians changed the dose because they anticipated a decrease in Tac C0 or because of Tac toxicity (side effects). Three months after conversion, 240 patients were still using Tac-OD. Their total daily Tac dose was comparable with that at the time of conversion: 4.0 6 1.8 versus 4.1 6 1.7 mg/d, P = 0.16. In the first 3 months after conversion, the daily Tac dose had been left unaltered in 149 but was increased in 51 and decreased in 40 patients based on Tac C0 measurements. Tac C0 decreased from 5.8 ng/mL at baseline to 5.1 ng/mL at month 3, corresponding to a 12% fall (P , 0.01). The doseadjusted Tac C0 (C0/D) also decreased by 14% (P , 0.01, Table 2). The analysis was repeated after exclusion of the 36 patients who were not converted on a 1:1 basis. Again, Tac C0 decreased significantly, decreasing from 5.7 to 5.0 ng/mL or by 12% (P , 0.01). Tac C0/D decreased from 1.43 to 1.25 ng/mL per mg/d (P , 0.01).
Clinical Outcomes
characteristics). Of these, 247 were converted to Tac-OD. Three patients never took Tac-OD for unknown reasons, and 1 patient declined conversion after signing informed consent. Of these 247 patients, 227 completed the 12-month follow-up (Fig. 1). During follow-up, 2 patients died, 5 were lost to follow-up, and in 13 patients treatment with Tac-OD was interrupted (in 8 cases because of side effects, in 4 for unknown reasons). These 12 patients were reconverted to Tac-TD. In 1 patient, treatment with Tac-OD was interrupted because of recurrent glomerulonephritis requiring cyclophosphamide and high-dose glucocorticoid treatment. Most patients (n = 211 or 85%) were converted from Tac-TD to Tac-OD on a 1:1 (milligram:milligram) total daily dose basis. However, in 36 cases, it was decided to change the daily Tac dose at conversion and was therefore increased in 25 and decreased in 11 patients. In 13 patients, the Tac dose was changed at the time of conversion because Tac C0 was
Ninety-one SAEs occurred in 62 patients (25.1%). Patient survival was 99.2%. One patient died from liver insufficiency caused by hepatitis C virus–related cirrhosis. The second patient died of unknown cause while on holiday. Neither of these deaths was suspected to be related to the use of Tac-OD. One-year graft survival censored for death was 100%. Two patients experienced a biopsy-proven acute rejection. The first patient had a type 1 acute cellular rejection occurring some 3½ years after transplantation and 8 months after conversion to Tac-OD, which was treated with methylprednisolone. The second patient experienced a type 1 acute cellular rejection occurring 3 months after conversion. This rejection may have been triggered by the conversion to Tac-OD as Tac exposure temporarily decreased to a nadir of 3.6 ng/mL. Three patients developed nonmelanoma skin cancer. Two patients experienced recurrent primary kidney disease (1 case of IgA nephropathy and 1 of p-ANCA–associated glomerulonephritis). Twenty-six SAEs were related to hospitalization for an infection. In 56 cases, other reasons necessitated hospitalization. Fifty-seven nonsevere adverse events (AEs) occurred in 52 (21.1%) patients. The most frequently reported AEs included skin-related disorders (n = 10, 4.0%) and infections (n = 17, 6.9%), most of which were urinary tract infections (n = 10, 4.0%). Renal function and proteinuria did not change during follow-up (Table 3). Renal function of the 12 patients who discontinued Tac-OD also remained stable (data not shown). Renal function of the patients (n = 114) who had a decrease in their Tac C0 also did not change after conversion: [48 (16–90) mL/min at baseline versus 47 (15–90) mL/min at month 3 after conversion, P = 0.13, versus 47 (12–90) mL/min at month 12 after conversion, P = 0.82]. Apart from a small decrease in high-density lipoprotein cholesterol, all other clinical and laboratory parameters were unaffected (Table 3).
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175 (69.7%)/76 (30.3%) 11 23 54 157 6 37
(4.4%) (9.2%) (21.5%) (62.5%) (2.4%) (5–312)*
29 193 13 8 8
(11.6%) (76.9%) (5.2%) (3.2%) (3.2%)
*Median (range). HLA, Human leukocyte antigen; MMF, mycophenolate mofetil.
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Intrapatient Variability in Tacrolimus Exposure
FIGURE 1. Flow chart.
Tac-OD was in general tolerated well, and only 8 patients discontinued Tac-OD because of side effects. The AEs that led to the discontinuation of Tac-OD were mild and included rash (n = 2), gastrointestinal complaints (n = 2), headache (n = 1), myalgia (n = 1), insomnia (n = 1), and worsening of eczema (n = 2).
Effect of Conversion to Tac-OD on Tac IPV To analyze the influence of Tac formulation on the IPV in Tac apparent oral clearance (hereafter referred to as Tac IPV), stricter inclusion criteria were applied. Eighty patients
were excluded, leaving a total of 167 patients for the IPV analyses. In 9 cases, ,3 samples were available after conversion because these patients were reconverted to Tac-TD. Seventy-one cases were excluded because the Tac-TD treatment phase was shorter than 9 months. As observed in the whole group, a significant decrease in Tac C0 (9.5%) and in Tac C0/D (10%) occurred between conversion and month 3, despite a stable Tac daily dose (Table 2). The mean number of available samples per patient was 6.3 6 2.3 (Tac-TD period) and 5.8 6 2.5 (TacOD phase) and was slightly higher before conversion
TABLE 2. The Pharmacokinetic Parameters at Conversion (t = 0) and After Conversion to Tac-OD Whole study population (n = 247) Tac dose (mg/d) Tac C0 (ng/mL) Tac C0/dose (ng/mL per mg/d) Patients available for IPV analysis (n = 167) Tac dose (mg/d) Tac C0 (ng/mL) Tac C0/dose (ng/mL per mg/d)
t=0
Month 3
Month 6
Month 9
Month 12
n = 247 4.0 6 1.8 5.8 6 1.5 1.46 6 1.88
n = 240 4.1 6 1.7 5.1 6 1.5* 1.26 6 1.85*
n = 237 4.0 6 1.7 5.1 6 1.4* 1.27 6 1.74*
n = 234 4.0 6 1.7 5.2 6 1.4* 1.31 6 1.73*
n = 227 4.0 6 1.7 4.9 6 1.5* 1.24 6 1.81*
3.8 6 1.7 5.3 6 1.4 1.39 6 1.92
3.9 6 1.7 4.8 6 1.5* 1.25 6 1.80*
3.8 6 1.7 4.9 6 1.4* 1.27 6 1.70*
3.9 6 1.7 5.0 6 1.3 1.33 6 1.72
3.8 6 1.7 4.6 6 1.5* 1.23 6 1.84*
All values are expressed as geometric mean with SD. The apparent oral clearance is calculated by taking the reciprocal of dose-corrected Tac C0 (eg, a Tac C0/dose of 1.4 ng/mL per mg/day gives an apparent oral clearance of 0.50 L/min). *Significant change (P , 0.05) comparing with the measurements at the conversion time point (t = 0).
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TABLE 3. Evolution of Clinical and Laboratory Parameters in the 12 Months After Conversion From Tac-TD to Tac-OD Conversion Plasma creatinine (mmol/L) eGFR (mL/min) Proteinuria (g/L) Protein/creatinine (mg/mmol) Hemoglobin (mmol/L) Fasting plasma glucose (mmol/L) Triglycerides (mmol/L) Total cholesterol (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg)
132 48 0.11 14.52 8.2 5.6 1.56 4.6 1.21 2.65 135 80
(55–324) (16–90) (0.02–3.42) (4.00–551.60) (4.9–11.0) (3.9–26.7) (0.46–6.88) (1.8–7.5) (0.33–4.86) (0.34–5.44) (80–191) (50–110)
Month 12 6 1 134 46 0.10 13.51 8.3 5.6 1.57 4.5 1.20 2.70 139 80
(57–464) (12–90) (0.01–6.88) (3.97–1186.20) (5.1–11.4) (3.8–22.2) (0.45–6.76) (2.5–7.5) (0.63–3.44) (1.20–5.43) (100–200) (58–104)
P 0.38 0.26 0.80 0.57 0.35 0.98 0.45 0.41 0.04 0.59 0.65 0.91
eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; protein/creatinine, urinary protein/urinary creatinine ratio.
(P = 0.02). In both phases, interpatient variability in IPV was considerable, with some individuals having a variability of ,5% and others .50%. The median IPV for Tac-TD was 17.9% (2.9%–51.4%) and for Tac-OD 16.8% (4.2%–64.1%), P = 0.25. Conversion to Tac-OD did not result in a change in geometric mean Tac IPV: 17.3% 6 1.7% versus 16.4% 6 1.6%, for the Tac-TD and Tac-OD phases, respectively, P = 0.31. The conversion also did not alter the distribution of the IPV (P = 0.12, Fig. 2). When the 71 patients with a Tac-TD phase ,9 months were included, again Tac IPV did not change after conversion to Tac-OD: the median IPV for
Tac-TD was 16.9% (1.5%–56.1%) and for Tac-OD 16.5% (4.1%–68.5%), P = 0.71. Patients were classified using the median Tac IPV before conversion (17.9%) as the cutoff. This resulted in 83 patients being classified as having low variability (mean: 11.7% 6 1.4%) and 84 as having a high variability (mean: 25.6% 6 1.3%). Using this same cutoff, after conversion, the number of patients in the low-variability group rose from 83 to 93 (11.8% 6 1.4%), whereas 74 patients ended up in the highvariability group (24.9% 6 1.3%). Before conversion, patients with high IPV had a higher number of Tac dose changes in the
FIGURE 2. Change of distribution (by 5% intervals) of Tac IPV before and after conversion from Tac-TD to Tac-OD.
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12 6 3-month observation period compared with patients with low IPV [median 0.5 (0–5) versus 0.0 (0–3), P = 0.02]. After conversion, there were no significant differences in the number of Tac-OD dose adjustments between the 2 groups: median 1.0 (0–4) versus 0.0 (0–3) for the low- and high-variability groups, respectively, P = 0.078. This same analysis restricted to the group of 84 patients with high variability before conversion demonstrated a significant decrease in IPV after conversion: 25.6% 6 1.3% versus 17.1% 6 1.6% (P , 0.01, Fig. 3B). This effect was even stronger when we included only those patients with an IPV in the upper quartile: IPV decreased from 31.8% 6 1.2% to 18.0% 6 1.6% in the Tac-OD phase (P , 0.01). The reverse was observed for the group of 83 patients who had a low Tac IPV before conversion: the IPV increased from 11.7% 6 1.4% (Tac-TD) to 15.8 6 1.6% (Tac-OD), P , 0.01 (Fig. 3C). Univariate analyses revealed that age, sex, time after transplantation, baseline creatinine, and hemoglobin concentration had no influence on IPV. Unfortunately, CYP3A5 genotype, which has been correlated with Tac dose requirement,14 was not available for this cohort. However, there was a direct proportional correlation between the number of samples and IPV and between the number of dose changes and IPV. In a regression analysis, the effect of switching from Tac-TD to Tac-OD on the IPV remained statistically significant at the same level after
Intrapatient Variability in Tacrolimus Exposure
adjustment for the number of dose changes and the number of samples. Subsequently, we investigated whether this observation was a treatment effect or whether it was caused by the RTM phenomenon. After conversion, patients with high variability in Tac exposure had a 0.1746 change (decrease) in IPV on the log scale, corresponding to 8.5% on normal scale. Using Equation 2 with st = 0.1263, ƿ = 0.05, population mean of 1.2386, c = 1.2538, f = 0.40, and F = 0.47, the estimated RTM effect was 0.1726 (98% of the observed decrease). Hence, it can be concluded that there was no real change in the IPV after conversion.
DISCUSSION This study demonstrates that converting stable RTRs from Tac-TD to Tac-OD is safe. Graft survival (censored for death) after conversion was 100%, and only 2 patients died from causes unrelated to the Tac formulation conversion. Renal function, proteinuria, glucose levels, and blood pressure did not change after conversion. Although a considerable number of SAEs occurred, this is not unusual for RTRs who are immunocompromised and frequently have multiple comorbidities. Tac-OD was tolerated well, treatment discontinuations because of AEs were infrequent, and drug-related side effects
FIGURE 3. The individual change of Tac IPV before and after conversion from Tac-TD to Tac-OD. A, All patients available for the IPV analysis (n = 167). B, Patients with high IPV before conversion (n = 84). C, Patients with low IPV before conversion (n = 83). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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Ther Drug Monit Volume 37, Number 2, April 2015
were mild. The nonrandomized design of this study is an obvious limitation, making a formal comparison regarding the safety of both formulations impossible. However, our findings are consistent with safety data of other conversion studies9,15–17 and of the phases 2 and 3 trials.18 Industry-sponsored trials performed in both stable and de novo RTRs showed that conversion from Tac-TD to TacOD on a 1:1 (milligram:milligram) daily dose basis yields comparable drug exposure [measured as either the area under the concentration versus time curve 0–24 hours (AUC0–24) or C0].19 However, more recent reports demonstrate that conversion to Tac-OD is associated with considerably lower Tac exposure (of up to 15%), necessitating occasional dose changes.19–21 In line with the latter observations, significantly lower Tac C0 and Tac C0/D were observed after conversion in this study. These discrepancies in the changes in Tac exposure after conversion likely relate to differences in inclusion criteria of the various trials, which were stricter in the earlier trials. The present study was a “real-world” conversion study, and only a few exclusion criteria applied. Apart from 1 patient who suffered from acute rejection shortly after conversion, there were no other cases of rejection that contributed to low Tac exposure. It can be argued that the observed lowering of Tac exposure after conversion is not clinically relevant. Nevertheless, to prevent the occasional case of marked overexposure or underexposure, at our center, we routinely measure Tac C0 1–2 weeks after conversion to Tac-OD. This study shows that conversion from Tac-TD to TacOD does not result in a lower Tac IPV, confirming the findings of Wehland et al7 and van Hooff et al,11 which were conducted in smaller patient groups. Other investigators have observed a lowering of Tac IPV after conversion.8–10 An important limitation of the study of Wu et al9 is the fact that the number of samples after conversion was larger than before conversion. By mathematical principle, the estimation of IPV (or %CV) will become more precise if the number of samples increases. In the study by Stifft et al,10 Tac IPV did not change after conversion when it was calculated using C0 but decreased when it was calculated using AUC0–24. In the study by Stifft et al, the decrease in Tac IPV, calculated using AUC0–24, was 3.2%, which, although statistically significantly different, may be considered not to be clinically relevant. In the present study, we chose to evaluate Tac exposure using C0 only because of reports demonstrating a significant correlation between AUC0–24 and C0 for both Tac formulations8,10,22,23 and because Tac C0 is the therapeutic drug monitoring parameter that is used most frequently in clinical practice. A change in Tac IPV may thus have remained undetected. The present study did, however, have a power of almost 100% to detect a difference in IPV (data not shown). In patients with a high Tac variability, conversion resulted in a significantly decreased IPV. This may have been caused by improved adherence as observed by Kuypers et al.3 We did not measure patient compliance directly. However, because the observed median IPV was not very high before conversion, we feel that the rate of medication adherence in the present selected population may have been high, with
1. Dew MA, DiMartini AF, De Vito Dabbs A, et al. Rates and risk factors for nonadherence to the medical regimen after adult solid organ transplantation. Transplantation. 2007;83:858–873. 2. Butler JA, Roderick P, Mullee M, et al. Frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review. Transplantation. 2004;77:769–776. 3. Kuypers DR, Peeters PC, Sennesael JJ, et al. Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring. Transplantation. 2013;95: 333–340. 4. Kahan BD. High variability of drug exposure: a biopharmaceutic risk factor for chronic rejection. Transplant Proc. 1998;30:1639–1641. 5. Borra LC, Roodnat JI, Kal JA, et al. High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation. Nephrol Dial Transplant. 2010;25:2757–2763. 6. Ro H, Min SI, Yang J, et al. Impact of tacrolimus intraindividual variability and CYP3A5 genetic polymorphism on acute rejection in kidney transplantation. Ther Drug Monit. 2012;34:680–685. 7. Wehland M, Bauer S, Brakemeier S, et al. Differential impact of the CYP3A5*1 and CYP3A5*3 alleles on pre-dose concentrations of two tacrolimus formulations. Pharmacogenet Genomics. 2011;21:179–184. 8. Alloway R, Steinberg S, Khalil K, et al. Conversion of stable kidney transplant recipients from a twice daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen. Transplant Proc. 2005; 37:867–870. 9. Wu MJ, Cheng CY, Chen CH, et al. Lower variability of tacrolimus trough concentration after conversion from prograf to advagraf in stable kidney transplant recipients. Transplantation. 2011;92:648–652. 10. Stifft F, Stolk LM, Undre N, et al. Lower variability in 24-hour exposure during once-daily compared to twice-daily tacrolimus formulation in kidney transplantation. Transplantation. 2014;97:775–780. 11. van Hooff J, Van der Walt I, Kallmeyer J, et al. Pharmacokinetics in stable kidney transplant recipients after conversion from twice-daily to once-daily tacrolimus formulations. Ther Drug Monit. 2012;34:46–52. 12. Barnett AG, van der Pols JC, Dobson AJ. Regression to the mean: what it is and how to deal with it. Int J Epidemiol. 2005;34:215–220. 13. Davis CE. The effect of regression to the mean in epidemiologic and clinical studies. Am J Epidemiol. 1976;104:493–498.
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little potential for further improvement by conversion to Tac-OD. Alternatively, reported changes in IPV after conversion may not have been a true treatment effect but rather the result of RTM. RTM is a statistical phenomenon that can make natural variation in repeated data that seem to reflect a real change. This occurs when unusually large or small measurements tend to be followed by measurements that are closer to the mean.12,13 Indeed, about 98% of the decrease in IPV we observed was explained by RTM and therefore not the result of conversion per se. Whether the RTM phenomenon also affected the results of previous studies cannot be determined. However, the chance that this phenomenon occurs increases when a nonrandomized, controlled, or noncrossover design is followed. In conclusion, conversion from the Tac-TD to the Tac-OD formulation on the same milligram-for-milligram daily dose basis significantly reduces Tac exposure but does not lower Tac IPV. Nonetheless, conversion to Tac-OD seems to be safe.
ACKNOWLEDGMENTS The authors are grateful to Mrs. I. Buijt for her statistical advice. REFERENCES
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Intrapatient Variability in Tacrolimus Exposure
14. Hesselink DA, Bouamar R, Elens L, et al. The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2014;53:123–139. 15. Guirado L, Cantarell C, Franco A, et al. Efficacy and safety of conversion from twice-daily to once-daily tacrolimus in a large cohort of stable kidney transplant recipients. Am J Transplant. 2011;11:1965–1971. 16. Alloway R, Steinberg S, Khalil K, et al. Two years postconversion from a prograf-based regimen to a once-daily tacrolimus extended-release formulation in stable kidney transplant recipients. Transplantation. 2007; 83:1648–1651. 17. Kurnatowska I, Krawczyk J, Oleksik T, et al. Tacrolimus dose and blood concentration variability in kidney transplant recipients undergoing conversion from twice daily to once daily modified release tacrolimus. Transplant Proc. 2011;43:2954–2956. 18. Kramer BK. Tacrolimus prolonged release in kidney transplantation. Expert Rev Clin Immunol. 2009;5:127–133.
19. Barraclough KA, Isbel NM, Johnson DW, et al. Once- versus twice-daily tacrolimus: are the formulations truly equivalent? Drugs. 2011;71:1561–1577. 20. Ho ET, Wong G, Craig JC, et al. Once-daily extended-release versus twice-daily standard-release tacrolimus in kidney transplant recipients: a systematic review. Transplantation. 2013;95:1120–1128. 21. Niioka T, Satoh S, Kagaya H, et al. Comparison of pharmacokinetics and pharmacogenetics of once- and twice-daily tacrolimus in the early stage after renal transplantation. Transplantation. 2012;94:1013–1019. 22. Florman S, Alloway R, Kalayoglu M, et al. Conversion of stable liver transplant recipients from a twice-daily Prograf-based regimen to a oncedaily modified release tacrolimus-based regimen. Transplant Proc. 2005; 37:1211–1213. 23. Wlodarczyk Z, Squifflet JP, Ostrowski M, et al. Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open-label trial. Am J Transplant. 2009; 9:2505–2513.
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